AB0024 PLURIPOTENCY MARKER PBX1 PREDICTS TREATMENT EFFECT IN RHEUMATOID ARTHRITIS
Authors: K. M. Andersson, E. Malmhäll-Bah, M. Erlandsson, V. Chandrasekaran, S. Töyrä Silfverswärd, R. Pullerits, M. I. Bokarewa
Journal: Annals of the Rheumatic Diseases (2022)

Background Accelerated immunosenescence with contraction of T cell repertoire, demise of thymic function and expansion of CD28 null T cells with poor T cell reconstitution is the hallmark of rheumatoid arthritis (RA) 1 . Objectives In this study we assessed if PBX1 transcription factor that maintains the pluripotency of hematopoietic stem cells could be used to predict treatment response in RA patients. Methods CD4 + T cells of 87 RA female patients (age, median 61y (23-76); disease duration, median 9y (0-45)) were isolated from the perpheral blood, activated with aCD3 and subjected to transcriptional analysis by RNAseq (Illumina). External RNAseq of CD4 + T cells of 80 RA patients (f 56, m 24) was used for validation. The genes differentially expressed (DEG, nominal p&lt;0.05) between PBX1 hi and PBX1 lo groups were identified by R-studio using Benjamini-Hochberg correction (Bioconductor, DESeq2 package). DEGs were clustered by covariance to identify PBX1 associated genes and biological processes. Clinical variates and treatment regimens in PBX1 hi and PBX1 lo groups were compared. Results The patients of PBX1 hi and PBX1 lo groups were of similar age and disease duration but differed in anti-rheumatic treatment. PBX1 hi group was often treated with conventional DMARDs and monotherapy, while PBX1 lo group was mostly treated with biologics and/or JAK-inhibitors in combination with cDMARDs (χ 2 , p=0.0099). This treatment led to sufficient disease control in both PBX1 groups (median DAS28; 2.6 and 2.7, respectively). In the external RA cohort of the patients resistant to conventional DMARDs, PBX1 hi patients had significantly fewer frequency of non-responders to anti-TNF treatment compared to PBX1 lo (χ 2 , p=0.026). Pathway analysis of the DEGs identified strong enrichment for regulation of transcription (cor.p=10 -23 ), RNA metabolic processes (cor.p=10 -18 ) and differentiation (cor.p=10 -7 ) in PBX1 hi CD4 + cells, which corresponds to the known biological properties of PBX1 2 . PBX1 hi CD4 + cells in both datasets had imprinted features of pluripotency 3 and expressed higher levels of KIT and CAT, low proliferation markers Ki67 and BIRC5, and had virtually no cytokine production. In the main cohort, PBX1 hi CD4 + cells were recognized by naïve T cell marks CD62L (SELL) and CD45 (PTPRC), and also PECAM1, CR2, and CD28, indicating recent thymic egress. In the validation cohort, PBX1 hi CD4 + cells were enriched with stem cell markers CD34, MEG3, and DNMT3B. Lineage specific TFs (TBET, GATA3, FOXP3, RORC) and cytokines (IFNG, TNF, IL10, IL17F, etc.) were accumulated in PBX1 lo CD4 + cells indicating terminally differentiated effector CD4 + T cells. Conclusion This study shows that enrichment with PBX1 hi CD4+ cells is associated with naïve pluripotent phenotype of CD4 lymphocytes. Patients with high PBX1 expression are less heavily treated and respond better to treatment. This suggests boosting of PBX1-expression to be a way of treating RA. References [1]Keotz K et al, PNAS 2000:97(16) 9203-9208. T cell homeostasis in patients with rheumatoid arthritis. [2]Veiga RN et al, J Mol Med (Berl) 2021:99(12) 1667-1680. PBX1: a key character of the hallmarks of cancer. [3]Bock C et al, Cell 2011:144(3) 439-452. Reference Maps of human ES and iPS cell variation enable high-throughput characterization of pluripotent cell lines Disclosure of Interests None declared